Edgewise Therapeutics has announced promising top-line data from its Phase 1 trial in healthy subjects and the single-dose arm of its Phase 2 CIRRUS-HCM trial involving patients with obstructive hypertrophic cardiomyopathy (HCM). The trials evaluated EDG-7500, a novel oral, selective, cardiac sarcomere modulator designed to slow early contraction velocity and improve cardiac relaxation in HCM patients. The data suggests EDG-7500 could offer a valuable advancement in treating obstructive HCM.
Phase 1 Trial Results
The Phase 1 trial was a placebo-controlled, single ascending dose (SAD) study with 48 healthy participants, receiving single doses of EDG-7500 ranging from 5 to 300 mg. The multiple ascending dose (MAD) portion included 24 healthy subjects receiving 25 to 100 mg once daily for 14 days. EDG-7500 was well-tolerated in both SAD and MAD groups, with no clinically significant changes in vital signs, clinical chemistry, hematology, or electrocardiograms. Importantly, there were no meaningful changes in left ventricular ejection fraction (LVEF) across a broad range of EDG-7500 exposures. The MAD portion showed a half-life of approximately 30 hours, with steady state achieved around 4 days after initiating once-daily dosing. Dose-proportional increases in exposure were generally observed in both SAD and MAD.
CIRRUS-HCM Trial Results
In Part A of the CIRRUS-HCM trial, patients with obstructive HCM received a single dose of 50, 100, or 200 mg of EDG-7500. The results showed a 67% mean reduction in resting left ventricular outflow tract pressure gradient (LVOT-G) and a 55% mean reduction in provokable (Valsalva) LVOT-G in patients receiving the 100 and 200 mg single doses. Notably, 60% of patients receiving 100 or 200 mg of EDG-7500 achieved LVOT gradients less than 30 mmHg at rest and less than 50 mmHg with Valsalva. The gradient reduction was achieved without a meaningful change in LVEF. Furthermore, a single dose of 200 mg EDG-7500 led to a 64% mean reduction in NT-proBNP, a key biomarker of heart failure.
Implications and Future Directions
These findings suggest that EDG-7500 has the potential to treat diseases of diastolic dysfunction, including non-obstructive HCM. According to Kevin Koch, Ph.D., President and Chief Executive Officer of Edgewise Therapeutics, the company believes their approach of observing gradient relief without reductions in LVEF could be a valuable advancement in obstructive HCM treatment. The company has initiated the 28-day part of the CIRRUS-HCM trial in patients with both obstructive and non-obstructive HCM and expects to report initial 28-day data in the first quarter of 2025.
Anjali T. Owens, M.D., Medical Director, Center for Inherited Cardiac Disease, Associate Professor of Medicine, University of Pennsylvania, and CIRRUS-HCM Investigator, emphasized the unmet need for patients with obstructive and non-obstructive HCM and expressed excitement about being part of the ongoing trial evaluating this novel treatment.
